Activity of Chemotherapy in Mucinous Epithelial Ovarian Cancer: A Retrospective Study

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1 Activity of Chemotherapy in Mucinous Epithelial Ovarian Cancer: A Retrospective Study CARMELA PISANO 1, STEFANO GREGGI 2, ROSA TAMBARO 1, SIMONA LOSITO 3, FRANCESCO IODICE 2, MASSIMO DI MAIO 1, ETTORE FERRARI 1, MARZIA FALANGA 1, ROBERTA FORMATO 1, VINCENZO ROSARIO IAFFAIOLI 1 and SANDRO PIGNATA 1 1 Medical Oncology B, 2 Gynecology and 3 Surgical Pathology, National Cancer Institute, via M.Semmola, 80131, Naples, Italy Abstract. Objective: Mucinous ovarian carcinoma has a poorer prognosis compared with other histological subtypes. The aim of this study was to evaluate, retrospectively, the activity of first-line and second-line chemotherapy in patients with mucinous ovarian cancer in a mono-institutional series. Patients and ªethods: In the period under survey ( ), 225 new patients with ovarian cancer were treated. Twenty-one out of these patients (9.3%) received a diagnosis of mucinous ovarian cancer. The median age, performance status, stage at diagnosis and residual disease after surgery were similar in the mucinous compared to the other histological groups (P=NS). Results: In mucinous ovarian cancer the grading of the tumors was 2 in 76% of the cases, while grade 3 was more frequent in the other subtypes (p<0.002). Eighty-five % of the patients had received carboplatin/paclitaxel, while the remaining cases had been treated with a cisplatin-based chemotherapy not containing paclitaxel. Two patients with early stage were treated with adjuvant chemotherapy and were not evaluable for response while 19 patients had measurable disease (12 pts) or were assessed at second-look (7 pts). Forty-seven % of the 19 patients experienced disease progression during first-line, while 31.5% and 10.5% complete and partial responses were recorded, respectively. Fifteen out of the 21 patients had progressed at the time of the analyses. Sixty % of the progressed patients were platinum-refractory, 3 cases were platinumsensitive and 3 platinum-resistant. The 3 platinum-sensitive patients were treated with single agent carboplatin without any response. No response was recorded with topotecan or liposomal doxorubicin when given as second- or third-line treatment in platinum-refractory/resistant patients. Conclusion: Correspondence to: Sandro Pignata, MD, Ph.D., Istituto Nazionale Tumori, via M.Semmola, 80131, Napoli, Italy. Tel: , Fax: , sandro.pignata@fondazionepascale.it Key Words: Ovarian cancer, mucinous, chemotherapy. Mucinous ovarian cancer has a poor response to chemotherapy both in the first-line and in the recurrence settings. Studies with alternative chemotherapy combinations are mandatory in this histological subgroup. The standard initial treatment of patients with advanced ovarian cancer is cytoreductive surgery, followed by combination chemotherapy with paclitaxel and a platinum compound (1, 2). After three randomized studies comparing carboplatin/paclitaxel with cisplatin/paclitaxel, the former schedule is considered the standard first-line treatment worldwide because of a better toxicity profile (3, 4). Despite the activity of this combination chemotherapy, which gives response rates up to 70%, the majority of patients die of recurrent disease. Therefore, a large proportion of patients are candidates for second-line therapy. A phase III study has recently shown that liposomal doxorubicin is at least as effective as topotecan in refractory/resistant ovarian cancer and these two drugs are the most frequently used in a second- and third-line setting (5). Patients with sensitive recurrent ovarian cancer are usually treated again with carboplatin/paclitaxel (6). Mucinous carcinoma of the ovary accounts for 7-14% of all primary epithelial ovarian cancer (1, 7). Patients with mucinous ovarian cancer generally undergo the same first- and secondline treatment as patients with other histological subtypes. However, it has recently been shown, in a series of 27 patients, that advanced mucinous ovarian carcinoma has a poor outcome with a significantly worse survival (7). Very few reports in the literature have been published on this topic and chemotherapy activity has been described in a limited number of patients and only in the first-line setting (7-9). Cloven et al. (10) have shown, "in vitro", that the frequency of extreme drug resistance to chemotherapeutic agents differs significantly among histological subtypes of epithelial ovarian cancer. These authors demonstrated that mucinous ovarian cancer cells are more frequently resistant /2005 $

2 Table I. Characteristics of the patients with mucinous ovarian cancer compared to other histological subtypes (# and %). Table II. Type of first line chemotherapy and objective response rate in patients with mucinous ovarian cancer. Mucinous Other histotypes n (%) 95% exact CL Age (years) Wilcoxon, p=0.479 median range ECOG performance status Chi-square, p= (61) 97 (47.5) 1 6 (28.5) 81 (39.7) 2 2 (10.5) 26 (12.7) FIGO stage at diagnosis Chi-square, p=0.86 I 1 (4.7) 18 (8.8) II 2 (9.4) 13 (6.3) III 13 (61.9) 119 (58.3) IV 5 (23.8) 54 (26.4) Grading Chi-square, p= (9.4) 8 (3.9) 2 16 (76.2) 72 (35.9) 3 3 (14.2) 124 (60.7) Result of cytor eductive surgery Chi-square, p=0.57 No surgery 2 (9.4) 41 (20.2) Optimal (<1 cm residual disease) 9 (42.8) 88 (43.1) Suboptimal (>1 cm residual disease) 10 (47.6) 75 (36.7) CA125 at diagnosis Chi-square, p=0.09 Normal 8 (38) 41 (20.1) (14) 19 (9.3) > (48) ) to cisplatin, but less frequently resistant to topotecan and doxorubicin compared to papillary serous tumors (10). The aim of this study was to evaluate, retrospectively, the activity of first-line and second-line chemotherapy in patients with mucinous ovarian cancer observed in a single institution. Patients and Methods In the period under survey ( ), 225 new patients with ovarian cancer were treated. The patients were operated on and treated with chemotherapy at the National Cancer Institute of Naples, Italy. Twenty-one of these patients (9.3%) received a diagnosis of mucinous ovarian cancer. All cases were analyzed by expert pathologists in order to rule out the possibility of secondary tumors. Two cases, in which the differential diagnosis between primary or secondary ovarian cancer was doubtful, were excluded. Type of first-line chemotherapy (21 patients) Platinum-based with paclitaxel 18 (85.7) Platinum-based without paclitaxel 3 (14.3) Objective response (19 patients evaluable*) Complete response 6 (31.5) Partial response 2 (10.5) Stable disease 2 (10.5) Progressive disease 9 (47.3) Overall response rate 8 (42.1) 23.1%-63.7% * 12 patients with measurable disease at radiology and 7 assessed at second look laparotomy or laparoscopy The main characteristics of the 21 patients analyzed are reported in Table I. Data were obtained using an electronic database with the following parameters available: age, performance status, stage at diagnosis, CA125 levels, histology, grading, degree of debulking at primary surgery, first-line chemotherapy and response to first-line chemotherapy. By our institutional algorithm, CT scan assessment was performed every 3 cycles of chemotherapy. During follow-up clinical and/or radiological examinations are scheduled every 3 months for the first 2 years and then every 6 months for another 3 years. Response to chemotherapy was reported according to WHO criteria (11) until the year 2001 and then by the RECIST criteria (12). Progressed patients were stratified according to platinum sensitivity as resistant (relapsed less than 1 year from completion of platinum-based treatment), refractory (progressed during platinum-based treatment or within 3 months from treatment end) or sensitive (progressed later than 12 months from treatment end) to prior platinum-containing chemotherapy. Overall survival was defined as the time elapsed between treatment start and the date of death or the date of last follow-up information for live patients. The median time to progression and overall survival were calculated by the Kaplan-Meier product limit method. Differences among baseline variables were analyzed by the Wilcoxon test and the Chi-square method. Differences were considered statistically significant when p<0.05. Results Table I shows the main clinical characteristics of the 21 patients with mucinous ovarian cancer compared with the other histological subtypes. The median age, performance status and stage at diagnosis were similar between the two groups. Most patients underwent primary cytoreductive surgery that was optimal, with residual tumor less than 1 cm 3502

3 Pisano et al: Chemotherapy for Mucinous Ovarian Cancer in diameter in 42% and 43% of the cases with mucinous and non-mucinous histology, respectively (p=ns). In mucinous ovarian cancer, the grading of the tumors was 2 in 76% of the cases, while grade 3 was more frequent in the other subtypes (p<0.0002). The majority of patients with mucinous tumors had normal CA125 levels at diagnosis and only 7 cases had CA125 values higher than 100 U/ml, although the difference was not statistically significant. Table II summarizes the type of first-line chemotherapy given to the 21 patients with mucinous ovarian cancer and the results in the evaluable patients. Eighty-five % of the patients had received carboplatin/paclitaxel, while the remaining cases had been treated with a cisplatin-based chemotherapy not containing paclitaxel. Two patients with early stage were treated with adjuvant chemotherapy and were not evaluable for response, while 19 patients had measurable disease (12 pts) or were assessed at second-look (7 pts). Forty-seven % of the 19 patients experienced disease progression while 31.5% and 10.5% complete and partial responses were recorded, respectively. This figure compares with a response rate of 85% in the other histological subtypes (data not shown). Fifteen out of 21 patients with mucinous ovarian cancer had progressed at the time of the analyses. Three patients with stage I-II disease and 3 with stage III are still alive without recurrence. Table III shows the details of the first progressions according to platinum sensitivity, and the second- and third-line chemotherapy given. Sixty % of the progressed patients were refractory having progressed during first-line chemotherapy, while 3 cases were platinumsensitive and 3 platinum-resistant. The 3 platinum-sensitive patients recurred between 18 and 24 months and had been optimally debulked at primary surgery. Platinum-sensitive patients were treated with single agent carboplatin without any response. No response was recorded with topotecan or liposomal doxorubicin in platinum-refractory/resistant recurrences when given as second-line treatment. Again, no response was observed among the 6 cases that underwent a third-line chemotherapy with either topotecan or liposomal doxorubicin. The only response recorded was in a platinumresistant patient treated with paclitaxel at recurrence after a first-line not containing this drug. Discussion This retrospective study confirms that mucinous ovarian cancer has a lower response rate to first-line chemotherapy compared to the other histological subtypes. The data also suggest that the response to second- and third-line chemotherapy is poor independently from platinum-free interval. Mucinous carcinomas of the ovary are reported to comprise 6-25% of ovarian carcinomas (mean 12%), Table III. Activity of second/third line chemotherapy in mucinous ovarian cancer according to platinum free interval. n (%) Type of first progression (15 patients) Platinum-refractory 9 (60) Platinum-resistant 3 (20) Platinum-sensitive 3 (20) Second-line chemotherapy (12 patients) Carboplatin 3 Paclitaxel 1 Liposomal doxorubicin 4 Topotecan 4 95% exact CL Response to second-line chemotherapy (11 patients evaluable) Complete response 0 (0) Partial response 1 (9) Stable disease 2 (0) Progressive disease 8 (0) Overall response rate 1 (9.1) 1.6%-37.7% Third-line chemotherapy (6 patients) Liposomal doxorubicin 3 Topotecan 3 Response to third-line chemotherapy (6 patients evaluable) Complete response 0 (0) Partial response 0 (0) Progressive disease 6 (100) although recent refinements in the interpretation of the histological features of noninvasive and metastatic mucinous carcinomas suggest that this may be an overestimate (13). Among metastatic tumors of the ovary, approximately 40% of cases originate from the colon (14). It is very important and often difficult to differentiate metastatic carcinomas from primary ovarian tumors, particularly in advanced stages. Several tumor markers have been advocated, but in some cases the sensitivity and specificity of these markers are not satisfactory (15). Clinical stage is the most important predictor of survival in mucinous ovarian carcinoma. The early stages confer a better overall prognosis for survival (13), while the advanced disease has been associated with a poorer survival compared to the other histological subgroups (7, 14, 16). In a recent case-controlled study Hess et al. (7) showed, in 27 mucinous cases and 54 controls, that patients with advanced mucinous ovarian cancer have a poorer response 3503

4 to platinum-based first-line chemotherapy compared with patients with other histological subtypes, along with a worse survival. In this series, only 37% of the patients were treated with a carboplatin/paclitaxel combination as first-line treatment, while the remainder received carboplatin alone or platinum plus anthracyclines. The overall response rate was 26% in first-line chemotherapy, while the response rate in second- and third-line chemotherapy was not reported (7). Here, we report the data of 21 consecutive patients with mucinous ovarian cancer treated in our institution. Comparing the differences between mucinous and the other histological subtypes, we found that the main statistically significant difference was in the grading of the tumors, which was grade 1 or 2 in 85% of the mucinous tumors, while it was mostly grade 3 in the other subgroups. No difference was observed in the rate of optimal debulking at primary surgery and stage at diagnosis. The CA125 values were normal in a large proportion of patients with mucinous ovarian cancer, suggesting that this tumor marker may not be as reliable as in the other histological types. In our series, differently from the data of Hess et al. (7), about 85% of patients were treated with a platinum/paclitaxel combination. However, we also found a response rate of 42%, that was significantly lower than that found in the other histological subgroups. In this study, we also report a very poor response rate to chemotherapy in the 11 patients treated in the second- and third-line setting, independently from the platinum-free interval. No response was observed to platinum/paclitaxel retreatment in the 3 patients with very late recurrence and with a high probability of response according to the Markman model (17). Again no response to liposomal doxorubicin or topotecan was observed in platinum-refractory/resistant patients treated as second- or third-line chemotherapy. Conventional parameters used to predict the clinical behavior of advanced ovarian cancer seem not to correlate with prognosis in mucinous carcinoma and thus appear to be inadequate. Several studies have shown that mucinous ovarian cancer has a different pattern of expression of some molecular factors compared to the other subtypes. It is possible that a better understanding of tumor biology may help in determining which patients with mucinous ovarian cancer would benefit from traditional chemotherapy or should receive alternative chemotherapy agents. Several studies have shown that RAS mutations (specifically at KRAS codon 12) are prevalent in ovarian cancers of mucinous histology, but not in tumors of nonmucinous histologies (18-22). On the contrary, mutation of p53, which is considered important in defining sensitivity to paclitaxel, is less frequent in mucinous tumors (23-25). Again, some studies have found that the expression of COX-2 was much less frequent in mucinous cancer than in serous and endometroid ovarian cancers (26-29). Treatment options tailored to the biology of mucinous ovarian cancer should be investigated in the future. The rarity of the disease should not discourage the assessment, in clinical trials, of the activity of different drugs, choosing first among those active in gastrointestinal cancer. Furthermore, "in vitro" drug response assays could be useful to select patients that are likely to be resistant to traditional chemotherapy, for whom an alternative, experimental treatment may be suggested. In conclusion, we confirm that mucinous ovarian cancer has a poor response to chemotherapy both in the first-line and the recurrence settings. Studies with alternative chemotherapy combinations are mandatory in this histological subgroup. 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